KR20060130689A - Mixed pharmaceutical compositions for inhibiting cognitive decline - Google Patents

Abstract

The present invention relates to component A), wherein (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7 of formula (I) -Trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof and component B), which further have a beneficial effect on brain function enhancers, inhibitors of acetyl-cholinesterase enzymes and / or cognitive processes A mixed pharmaceutical composition for inhibiting a decline in cognitive function comprising a pharmaceutically active ingredient of together with a suitable inert pharmaceutical carrier and / or adjuvant. The mixed pharmaceutical composition according to the present invention is particularly useful for diseases exhibiting symptoms similar to Alzheimer's disease or Alzheimer's disease, diseases with dysfunction of intellectual ability (for example, mental decline in schizophrenia), mental decline in the elderly (senile dementia) Can be used for mental decline by Korshakov syndrome, Huntington's syndrome, Parkinson's syndrome or alcoholism.

Description

{COMBINED PHARMACEUTICAL COMPOSITION FOR THE INHIBITION OF THE DECLINE OF COGNITIVE FUNCTIONS}

The present invention relates to a mixed pharmaceutical composition for inhibiting the decline of cognitive function.

(1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1 of formula (I) ] Heptane (international non-proprietary name: deramciclane) is an anti-anxiety pharmaceutically active ingredient under the general formula of HU 179,174:

Deramcyclane preparation is disclosed in HU 212,274.

Deramcyclane has shown significant effects in various depression and stress animal models. In a drinking test provided by Vogel, deramcyclane was active at 1 and 10 mg / kg after oral administration [ Gacsalyi et al., Receptor binding profile and anxiolytic activity of deramciclan (EGIS-3886) in animal models, Drug Dev . Res. 40: p. 338-348 (1997 ) In the social interaction model, the compound increased the time spent on social interaction after 0.7 mg / kg single oral treatment [ Crawley, JN Neuropharmacological specifity of a simple modl of anxiety for The behavioural actions of benzodiazepine, Pharmacol.Biochem.Behavior, 15: p. 695-699 (1981) , demonstrated that deramcyclane was active at a single oral dose of 3 mg / kg sc.marble burying model) [ Broekkamp, CL et al, Major Tranquillizers Can Be Distinguished from Minor Tranquillisers on the Basis of Effects on Marble Burying and Swim-Induced Grooming in Mice.Eur. J. Pharmacol. 126: p.2223-229 (1986) ] In, the molecule was active at 10 and 30 m / kg after oral treatment.

In relation to the activity mechanism, the compound is significantly bound to the central 5-HT _2C and 5-HT _2A receptors ( Gacsalyi et al., Receptor binding profile and anxiolytic activity of deramciclane (EGIS-3886) in animal models, Drug Dev. Res. 40: p . 338-348 (1997) ].

Many clinical studies and observations have shown that diseases and / or senile dementia characterized by intellectual and mental dysfunction are often accompanied by emotional areas and mood abnormalities and disorders.

Changes in cognitive function that affect high nervous system activity can lead to disorders of adaptation leading to anxiety and / or depression.

According to the literature, anxiety is present in 68-71% of patients with Alzheimer's disease and promotes cognitive decline . Ferretti et al., Anxiety and Alzheimer's disease. J. Geriatr. Psychiatry. Neurol., Spring, 14 (1), 52-58 (2001) ].

In patients with Huntington's disease , the predominant of the very high frequency of neuropsychiatric symptoms that occur is anxiety and discomfort . Paulsen et al., Neuropsychiatric aspects of Huntington's disease. J. Neurol. Neurosurg. Psychiatry., 71 (3), 310-314, (2001) ].

In dementia of different origins, anxiety is treated by adjuvant drug therapy. Rojas-Fernandez et al., Pharmacotherapy of behavioural and psychological symptoms of dementia. Pharmacotherapy, 21 (1) 74-102, (2001) ].

Summary of the Invention

According to the invention, as component A), (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7, of formula (I) 7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof and component B), which are advantageous for inhibitors and / or cognitive processes of nootropic, acetyl-cholinesterase enzymes Mixed pharmaceutical compositions are provided for inhibiting the decline in cognitive function comprising additional pharmaceutically active ingredients that work together with suitable inert pharmaceutical carriers and / or adjuvants.

The advantages of the mixed pharmaceutical composition of the present invention are that the life of the patient being treated by having a beneficial effect on cognitive function (memory, attention, cognition, learning), and at the same time having a beneficial effect on the emotional area and mood The quality is significantly increased. A further advantage of the mixed pharmaceutical compositions of the present invention is that the patients to be treated are generally elderly people who have problems receiving different types of medication. This can be solved by the mixed pharmaceutical composition of the present invention, which is sufficient to cope with the disease with a single medicine and can give a better satisfaction to the patient.

The present invention provides an anti-anxiety, antistress and fear reduction effect of deramcyclane of formula (I) or a suitable acid addition salt thereof used as component A) and a brain function improving agent, acetyl, which has a beneficial effect on the cognitive process used as component B). It is based on the recognition that the effects of inhibitors of cholinesterase enzymes, or other medications, mutually enhance the effects of each other.

The mixed pharmaceutical compositions of the present invention can be used for the following indications: diseases exhibiting symptoms similar to Alzheimer's disease or Alzheimer's disease, diseases with dysfunction of intellectual ability (eg, mental decline in schizophrenia), mental power in older people Decline (senile dementia), Korshakov's syndrome, Huntington's syndrome, Parkinson's syndrome or mental decline due to alcoholism.

The mixed pharmaceutical composition according to the invention is preferably formulated as component A) (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7, 7-trimethylbicyclo [2.2.1] heptan-2- (E) -butenedioate (1: 1).

The mixed pharmaceutical composition according to the invention is particularly preferably used as component A) (1R, 3S, 4R)-(-)-3- [2-N, N- (dimethylaminoethyl)]-of formula (II) (1R, 2S, 4R)-(-)-2- containing 0.2% or less of 1,7,7-trimethylbicyclo [2.2.1] heptan-2-one or a pharmaceutically acceptable acid addition salt thereof [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof:

According to a particularly preferred embodiment of the invention, the mixed pharmaceutical composition is component A), wherein (1R, 3S, 4R)-(-)-3- [2-N, N- (dimethylaminoethyl)]-1,7 (1R, 2S, 4R)-(-)-containing 0.2% or less of, 7-trimethylbicyclo [2.2.1] heptan-2-one-2- (E) -butenedioate (1: 1) 2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptan-2- (E) -butenedioate (1: 1) Include.

The mixed pharmaceutical composition according to the invention comprises, as component B), a brain function improving agent, an inhibitor of acetylcholinesterase enzyme and / or an additional pharmaceutically active ingredient having a beneficial effect on the cognitive process.

As a brain function improving agent, preferably, piracetam, but not anracetam, oxiracetam or pramiracetam can be used.

As an inhibitor of the acetylcholinesterase enzyme, preferably galantamine, rivastigmin or donzezepil can be used.

As component B), further, vinpocetin, calcium antagonists (e.g. nifedipin, nimodipin, amlodipin, felodipin, etc.) or antioxidants (e.g. Vitamin E) may be used.

The term "pharmaceutically acceptable acid addition salt" relates to salts formed with pharmaceutically acceptable inorganic or organic acids. For salt formation, for example, hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, fumaric acid, maleic acid, succinic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be used. (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] of formula (I) Heptane is particularly advantageously in the form of fumarate, i.e. (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7- Trimethylbicyclo [2.2.1] heptan-2- (E) -butenedioate (1: 1).

(1R, 3S, 4R)-(-)-3- [2-N, N- (dimethylaminoethyl)]-1,7,7-trimethylbicyclo [2.2.1] heptan-2 of formula (II) (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl containing up to 0.2% of -one or a pharmaceutically acceptable acid addition salt thereof 1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof is disclosed in the Hungarian patent application HU 1559/99.

Pharmaceutical compositions according to the present invention can be prepared in the form of herbals commonly used in the pharmaceutical industry. Such pharmaceutical compositions may be in solid or liquid form (eg, tablets, coated tablets, dragees, capsules, solutions, etc.). The pharmaceutical composition may be administered orally or parenterally, preferably orally. Mixed pharmaceutical compositions according to the invention can be prepared as is known in the pharmaceutical industry.

According to a further aspect of the present invention, there is provided a method for preparing a pharmaceutical composition for inhibiting a decline in cognitive function, as component A) (1R, 2S, 4R)-(-)-2- [N, N- (dimethyl Aminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), a brain function improving agent, acetylcholinestera Methods are provided that include mixing an inhibitor and / or a further pharmaceutically active ingredient having a beneficial effect on the cognitive process with an inert pharmaceutical carrier and / or adjuvant and making the mixture in herbal form.

According to a further aspect of the invention, as component A), (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2 for suppressing the decline of cognitive function -Phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), a brain function improving agent, an inhibitor of acetylcholinesterase enzyme and / or The use of a combination comprising additional pharmaceutically active ingredients having a beneficial effect on the recognition process is provided.

According to a further aspect of the invention, as component A) for the preparation of a pharmaceutical composition for inhibiting the decline of cognitive function, (1R, 2S, 4R)-(-)-2- [N, N- (dimethylamino Ethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), a brain function improving agent, acetylcholinesterase The use of combinations comprising inhibitors of enzymes and / or further pharmaceutically active ingredients having a beneficial effect on the recognition process is provided.

According to a further aspect of the invention, as a method for suppressing the decline of cognitive function, as component A) (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)] -2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), a brain function improving agent, an inhibitor of acetylcholinesterase enzyme, and And / or a method comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a combination comprising additional pharmaceutically active ingredients having a beneficial effect on the cognitive process.

According to a further aspect of the invention, (1R, 2S, 4R) for augmenting the effects of brain function enhancers, inhibitors of acetylcholinesterase enzymes and / or further pharmaceutically active ingredients which have a beneficial effect on cognitive processes, )-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof Use is provided.

The invention will be described in more detail in the following examples, but the scope of protection should not be limited to these examples.

Example 1

Combination of Deramcyclane and Galantamine

Preferred dosage ranges are 0.1 to 50 mg / die of deramcyclane and 8 to 32 mg / die of galantamine. More preferred dosage ranges are deram cyclanes of 1 to 30 mg / di and galantamine of 10 to 25 mg / di. Most preferred dose ranges are deramcyclanes of 2-10 mg / di and galantamine of 10-20 mg / di.

Example 2

Combination of Deramcyclane and Piracetam

Preferred dosage ranges are 0.1 to 50 mg / die of deramcyclane and 100 to 1500 mg / die of piracetam. More preferred dosage ranges are 1 to 30 mg / die of deramcyclane and 500 to 1200 mg / die of piracetam. Most preferred dose ranges are deramcyclanes of 2 to 10 mg / die and pyracetam of 750 to 1000 mg / die.

Example 3

Combination of Deramcyclane and Donzephile

Preferred dosage ranges are deramcyclanes of 0.1 to 50 mg / di and donezephile of 0.5 to 10 mg / di. More preferred dosage ranges are 1 to 10 mg / die of deramcyclane and 1 to 10 mg / die of donezefil. Most preferred dose ranges are deramcyclanes of 2 to 10 mg / die and donezephile of 5 to 10 mg / die.

Example 4

Combination of Deramcyclane and Vinpocetin

Preferred dosage ranges are 0.1 to 50 mg / die of deramcyclane and 1 to 50 mg / die of vinpocetin. More preferred dosage ranges are 1 to 30 mg / die of deramcyclane and 5 to 40 mg / die of vinpocetin. Most preferred dose ranges are deramcyclanes of 2 to 10 mg / di and vinpocetin of 10 to 30 mg / di.

Example 5

Combination of Deramcyclane and Vitamin E (Antioxidant)

Preferred dosage ranges are deramcyclanes of 0.1 to 50 mg / di and pyracetam of 1 to 1300 mg / di. More preferred dose ranges are 1 to 30 mg / die of deramcyclane and 50 to 300 mg / die of piracetam. Most preferred dose ranges are deramcyclanes of 2 to 10 mg / die and pyracetam of 100 to 300 mg / die.

Claims (11)

 As component A), (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethyl ratio of formula (I) Cyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof and component B), which further have a beneficial effect on the nootropic, inhibitors of acetyl-cholinesterase enzyme and / or cognitive processes A mixed pharmaceutical composition for inhibiting decline in cognitive function, comprising a pharmaceutically active ingredient of, together with a suitable inert pharmaceutical carrier and / or adjuvant:

The method of claim 1, further comprising a disease exhibiting symptoms similar to Alzheimer's disease or Alzheimer's disease, a disease accompanied by intellectual dysfunction (e.g. mental decline in schizophrenia), mental decline in the elderly (elderly dementia), Corsha Mixed pharmaceutical composition used to treat mental decline due to Cop syndrome, Huntington's syndrome, Parkinson's syndrome or alcoholism. The method according to claim 1 or 2, wherein as component A), (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7, A mixed pharmaceutical composition comprising 7-trimethylbicyclo [2.2.1] heptan-2- (E) -butenedioate (1: 1). A compound according to claim 1, wherein as component A), (1R, 3S, 4R)-(-)-3- [2-N, N- (dimethylaminoethyl)]-1,7,7 of formula (II) (1R, 2S, 4R)-(-)-2- [N, N- containing up to 0.2% of -trimethylbicyclo [2.2.1] heptan-2-one or a pharmaceutically acceptable acid addition salt thereof (Dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof

The compound according to claim 4, wherein (1R, 3S, 4R)-(-)-3- [2-N, N- (dimethylaminoethyl)]-1,7,7-trimethylbicyclo [2.2.1] heptane- (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy) containing not less than 0.2% of 2-one-2- (E) -butenedioate (1: 1) ] -2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptan-2- (E) -butenedioate (1: 1). 6. The component B) according to claim 1, wherein, as component B), piracetam, ananiracetam, oxiracetam, pramiracetam, galantamine A mixed pharmaceutical composition comprising rivastigmin, donezepil, vinpocetin, calcium antagonist or antioxidant. A method for preparing a pharmaceutical composition for inhibiting the decline of cognitive function, comprising (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl as component A) -1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), an inhibitor and / or cognitive process of a brain function improving agent, an acetylcholinesterase enzyme A further pharmaceutically active ingredient having a beneficial effect in admixing with an inert pharmaceutical carrier and / or adjuvant and making the mixture in herbal form. (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7- as component A) for suppressing the decline of cognitive function Trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), which further has a beneficial effect on brain function enhancers, inhibitors of acetylcholinesterase enzymes and / or cognitive processes Use of a combination comprising a pharmaceutically active ingredient.  (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl- as component A) for the manufacture of a pharmaceutical composition for inhibiting the decline of cognitive function 1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), an inhibitor and / or cognitive process of a brain function improving agent, an acetylcholinesterase enzyme Use of a combination comprising a further pharmaceutically active ingredient having an advantageous effect.  As a method for suppressing the decline of cognitive function, as component A) (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7, 7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), which have a beneficial effect on brain function enhancers, inhibitors of acetylcholinesterase enzymes and / or cognitive processes A method comprising administering a pharmaceutically effective amount of a combination comprising additional pharmaceutically active ingredients to a patient in need of such treatment. (1R, 2S, 4R)-(-)-2- [to enhance the effects of brain function enhancers, inhibitors of acetylcholinesterase enzymes and / or additional pharmaceutically active ingredients that have a beneficial effect on cognitive processes. Use of N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof.